In this investigation the reaction properties of human sickle cell hemoglobin (HbS) will be studied by means of measurements of oxidation-reduction potentials of the ferrohemoglobin S/ferrohemoglobin S system. Previous investigations have shown that the oxidation reaction of ferrohemoglobin resembles oxygenation and other ligand equilibria in many respects, although not identical in every detail. The effects of variations in experimental conditions, such as pH and concentrations of organic phosphates, other ions or carbon dioxide, and of procedures and reagents which have been reported to effect the sickling phenomenon will be investigated. These include treatment with substituted amides, cyanate, amino acids (e.g., phenylalanine, tryptophan, arginine) and peptides containing them (e.g., Phe-Phe-Arg), sugars, aldehydes, acetylating agents (e.g., aspirins) and sulfhydryl reagents (e.g., cystamine). Particular attention will be paid to observing the effects of the above procedures and reagents at higher concentrations of Hb S, in the neighborhood of the minimum gelling concentration, especially if higher concentrations of Hb S affect the oxidation-reduction equilibrium of Hb S, as has been observed in the oxygenation reaction. The effects of these procedures and reagents on oxygenation and other ligand equilibria of Hb S, and on the corresponding reaction properties of human adult hemoglobin (Hb A) or other hemoglobins, native or modified (e.g., Hb A1c) will be determined whenever such comparisons or controls are necessary or desirable.